Establishment and maintenance of normal heart cell function is essential to the survival of all higher organisms. During normal development, cells destined to become cardiac muscle cells undergo a process of differentiation whereby they form highly organized myofibrils capable of constant, rhythmic contraction. Myofibrillogenesis refers to the process whereby these fibrils are formed. In disease conditions affecting heart muscle, such as heart attack, stroke and congenital abnormalities, healthy heart cells fail to develop or are lost. Understanding of the mechanisms underlying control of myofibrillogenesis and cardiac muscle cell differentiation holds promise for restoring damaged heart muscle.
Previous studies have identified a cardiac mutant in a salamander, the Mexican axolotl with a defect in myofibrillogenesis. In this model, a cardiac lethal gene c is expressed in homozygous recessive animals. Matings between heterozygous parents (+/c×+/c) provide 25% mutant embryos (c/c) which are first distinguishable from their normal siblings (+/+ or +/c) at stage 34, when normal embryos develop contracting hearts. Mutant embryos form hearts that fail to beat and subsequently die from lack of circulation. The normal siblings mature to adulthood, exhibiting no obvious abnormalities (Humphrey, 1968).
Embryonic heart development in this species proceeds by a two-step mechanism (Smith and Armstrong, 1990). The first step, occurring during neurulation, is endoderm-dependent and directs early cardiac morphogenesis. This step is apparently normal in cardiac mutant hearts, which undergo early morphogenesis that is indistinguishable from that of normal hearts (Lemanski, 1973; Fransen and Lemanski, 1988). The second step involves myofibrillogenesis and the completion of differentiation into muscle tissue. In the mutant animals, the hearts become distended and thin-walled after heartbeat stage 35. The embryos subsequently develop ascites and survive only to stage 41, about 20 days after the normal time of onset of heart beating. However, mutant embryos swim normally, indicating that gene c does not affect skeletal muscle.
As the elderly population increases, and as larger segments of the population are subjected to high-stress employment situations, cardiovascular disease is becoming increasingly prevalent. The need for development of new therapeutic methods for restoring heart muscle cells continues to rise. Promising technologies of the future, such as replacement of damaged heart cells with cardiac cells grown in culture, are dependent upon finding the molecular keys to inducing a cardiac muscle cell phenotype.